Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide and amino acid sequences referred to in the specification are defined following the bibliography.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
The preferred haempoietin receptor of the present invention is referred to herein as “NR4”. The NR4 receptor interacts with IL-13 and is referred to herein as the EL-13 receptor or more particularly the IL-13 receptor α-chain (IL-13Rα). These terms are used interchangeably throughout the subject specification. The species from which a particular NR4 is derived is given in single letter abbreviation. For example, murine is “M” and human is “H”. A recombinant form may have the prefix “r”.
The rapidly increasing sophistication of recombinant DNA techniques is greatly facilitating research into the medical and allied health fields. Cytokine research is of particular importance, especially as these molecules regulate the proliferation, differentiation and function of a wide variety of cells. Administration of recombinant cytokines or regulating cytokine function and/or synthesis is increasingly becoming the focus of medical research into the treatment of a range of disease conditions.
Despite the discovery of a range of cytokines and other secreted regulators of cell function, comparatively few cytokines are directly used or targeted in therapeutic regimes. One reason for this is the pleiotropic nature of many cytokines. For example, interleukin (IL)-11 is a functionally pleiotropic molecule (1,2), initially characterized by its ability to stimulate proliferation of the IL-6-dependent plasmacytoma cell line, T11 65 (3). Other biological actions of IL-11 include induction of multipotential haemopoietin progenitor cell proliferation (4,5,6), enhancement of megakaryocyte and platelet formation (7,8,9,10), stimulation of acute phase protein synthesis (11) and inhibition of adipocyte lipoprotein lipase activity (12, 13).
Interleukin-13 (IL-13) is another important cytokine which shares a number of structural characteristics with interleukin-4 (IL-4) [reviewed in 14 and 15]. The genes for IL-4 and IL-13 have a related intron/exon structure and are located close together on chromosome 5 in the human and the syntenic region of chromosome 11 in the mouse (14, 15). At the protein level, IL-4 and IL-13 share approximately 30% amino acid identity, including four cysteine residues. Biologically, IL-13 and IL-4 are also similar, being produced by activated T-cells and acting upon, for example, macrophages to induce differentiation and suppress the production of inflammatory cytokines. Additionally, human IL-13 may act as a co-stimulatory signal for B-cell proliferation and affect immunoglobulin isotype switching (14, 15). The diverse and pleiotropic function of IL-13 and other haemopoietic cytokines makes this group important to study, especially at the level of interaction of the cytokine with its receptors. Manipulation and control of cytokine receptors and of cytokine-receptor interaction is potentially very important in many therapeutic situations, especially where the target cytokine is functionally pleiotropic and it is desired to block certain functions of a target cytokine but not all functions.
Research into IL-13 and its receptor has been hampered due to the inability to clone genetic sequences encoding all or part of the IL-13 receptor. In accordance with the present invention, genetic sequences have now been cloned encoding the IL-13 receptor α-chain, a receptor subunit which is also shared with the IL-4 receptor. The availability of these genetic sequences permits the development of a range of therapeutic and diagnostic agents capable of modulating or monitoring IL-13 activity as well as the activity of cytokines related to IL-13 at the level of structure or function. In accordance with the present invention, an example of a cytokine related in structure and function to IL-13 is IL-4.